Over the past decade, interest in aldosterone as a pathogenic hormone in cardiovascular disease has occurred. In addition to its well-known effect on blood pressure and on sodium (Na+), potassium (K+) and hydrogen (H+) homeostasis, aldosterone is associated with cardiac hypertrophy, fibrosis, nephropathy and strokes. Some of these effects may be secondary to potentiation of the release of plasminogen activator inhibitor, type 1 (PAI-1). Thus, derangement in aldosterone secretion may be an important link between cardiovascular damage and hypertension and heart failure. Angiotensin II (AngII) has several effects similar to aldosterone. Since AngII also regulates aldosterone secretion, the interaction of these two potential cardiovascular risk factors needs to be clarified. The overall goal of this proposal is to test the hypothesis that aldosterone is a cardiovascular risk hormone. The results of these studies will be relevant for several human disease, e.g., congestive heart failure, renal failure, atherosclerosis, and hypertension. To accomplish this overall goal, they will address three groups of specific aims. First, they will establish the principle that aldosterone induces cardiovascular damage and define its extent. They will use three rat models: 1) nitric oxide synthase inhibition with AngII and Na+ supplementation, 2) uninephrectomy with aldosterone and Na+ supplementation, and 3) uninephrectomy with AngII and Na+ supplementation. Preliminary data document that all three models induced cardiovascular damage, and aldosterone is a likely mediator. Second, they will define some of the underlying mechanisms. Two approaches will be used: 1) they will determine the level of Na+ intake required to induce cardiovascular damage, assess if increasing K+ intake is equivalent to blocking aldosterone's effect in inhibiting the damage, and determine the duration of exposure to the experimental paradigm necessary to produce damage. 2) they will assess the role of intermediaries, including tissue AngII, PAI-1, transforming growth factor-beta 1, collagen synthesis, Na+, H+ exchange and Na+, K+ ATPase using cellular and molecular techniques, including mouse knock-out models. Third, they will determine whether established cardiovascular damage can be reversed by modifying aldosterone's action. Their results should better define the rationale for the use of mineralocorticoid antagonists in the prophylaxis of damage to the heart, the kidney and other tissues when aldosterone levels are inappropriately elevated relative to the level of Na+ intake.